Cisplatin, cis-diamminedichloroplatinum (commercial name is Platinol®), has been used as a chemotherapeutic agent for about twenty years since the discovery of its anti-tumor activity by B. Rosenberg. The Oct. 23, 1995 issue of Chemical & Engineering News reported, “Cisplatin was first synthesized in the 1800s, but its anticancer activity was not discovered until the 1960s . . . In 1979, it was approved by the Food and Drug Administration (FDA) for clinical treatment of testicular and ovarian tumors and cancers of the head and neck”. The Physician's Desk Reference states that cisplatin can be used to treat testicular cancer, ovarian cancer, and bladder cancer.
As a first generation platinum drug, Cisplatin is still being widely used because of its efficacy. However, it is far from being a perfect anticancer drug. Carboplatin (Paraplatin®), was approved by the FDA as the second platinum drug. It appears to have a better therapeutic index than Cisplatin and is more widely prescribed than cisplatin. However, Carboplatin still has significant toxicity and can incur drug resistance from repeat treatment. Recent trends in this field indicate that there may be a renewed interest in finding a significantly improved platinum drug. The third platinum drug, oxaliplatin, has been on European market for a couple of years. Its efficacy is lower than the current platinum drug, but it appears to have lower toxicity. Structures of cisplatin, carboplatin, and oxaliplatin are shown below:
Problems Associated with Today's Anticancer Platinum Drugs
Cisplatin is known to function as an inhibitor to the DNA replication process; without the ability to replicate, cancer cells eventually die. It is believed that the inhibition is due to the intra-strand cross-linkage between Cisplatin and DNA through the two labile Pt—Cl bonds, especially during the DNA replication process. However, Cisplatin is not very selective in attacking the cells as is carboplatin. As cisplatin and carboplatin destroy cancerous cells, they also damage normal cells.
One of the most critical challenges to improving platinum drugs is to significantly improve the therapeutic index (largely defined as the efficacy/toxicity ratio). An ideal anticancer platinum drug should have a good therapeutic index. Unfortunately, a platinum drug works essentially by killing cancer cells through its cytotoxicity. Thus, increasing the efficacy of such a drug is likely to increase the side effects due to the increased toxicity. This efficacy-toxicity dilemma has hampered the real improvement of platinum drugs for many years.